Integrative functional genomic analyses identify genetic variants influencing skin pigmentation in Africans

Description

Abstract

Skin color is highly variable in Africans, yet little is known about the underlying molecular mechanism. We applied massively parallel reporter assays to screen 1,157 candidate variants influencing skin pigmentation in Africans and identified 165 SNPs showing differential regulatory activities between alleles. Combining Hi-C, CRISPR-based editing, and melanin assays, we identified regulatory elements for MFSD12, HMG20B, OCA2, MITF, LEF1, TRPS1, BLOC1S6, and CYB561A3 that impact melanin levels in vitro and modulate human skin color. We found that independent mutations in an OCA2 enhancer contribute to the evolution of human skin color diversity and detect signals of local adaptation at enhancers of MITF, LEF1 and TRPS1 which may contribute to the light skin color of southern Khoesan-speaking populations. Additionally, we identified CYB561A3 as a novel pigmentation regulator that impacts genes involved in oxidative phosphorylation and melanogenesis. These results provide insights into the mechanisms underlying human skin color diversity and adaptive evolution.